Elsevier

Neuropharmacology

Volume 75, December 2013, Pages 479-490
Neuropharmacology

Invited review
Regulation of connexin hemichannel activity by membrane potential and the extracellular calcium in health and disease

https://doi.org/10.1016/j.neuropharm.2013.03.040Get rights and content

Highlights

  • Ubiquitous presence of functional hemichannels at the cell surface as a normal phase in the connexin life cycle.

  • Strict regulation of hemichannel activity by membrane potential and extracellular calcium.

  • Update of mechanisms and molecular basis of hemichannel voltage-gating and of regulation by calcium.

  • Hemichannel dysfunction in “connexinopathies”.

Abstract

Connexins are thought to solely mediate cell-to-cell communication by forming gap junction channels composed of two membrane-spanning hemichannels positioned end-to-end. However, many if not all connexin isoforms also form functional hemichannels (i.e., the precursors of complete channels) that mediate the rapid exchange of ions, second messengers and metabolites between the cell interior and the interstitial space. Electrical and molecular signaling via connexin hemichannels is now widely recognized to be important in many physiological scenarios and pathological conditions. Indeed, mutations in connexins that alter hemichannel function have been implicated in several diseases. Here, we present a comprehensive overview of how hemichannel activity is tightly regulated by membrane potential and the external calcium concentration. In addition, we discuss the genetic mutations known to alter hemichannel function and their deleterious effects, of which a better understanding is necessary to develop novel therapeutic approaches for diseases caused by hemichannel dysfunction.

This article is part of the Special Issue Section entitled ‘Current Pharmacology of Gap Junction Channels and Hemichannels’.

Section snippets

The ubiquitous presence of functional hemichannels at the cell surface is a normal phase in the connexin life cycle

Connexins (Cx) are proteins encoded by a multigene family that typically form cell–cell channels. To date, 21 Cx genes have been identified in the human genome and most of their Cx orthologues have been described in other vertebrate species. The assembly of connexins into gap junction channels (GJC) occurs in two main stages. Connexins first oligomerize into hexameric hemichannels (HC) in the Golgi apparatus, from where they are transported to the cell surface in vesicles and they fuse to the

Regulation of hemichannel activity by membrane potential and extracellular calcium

The electrophysiological properties of Cx HCs have been extensively characterized. Most HCs are activated by depolarization of the membrane potential (Vm), and channel opening is critically dependent on the concentration of extracellular Ca2+ ions ([Ca2+]e) and other divalent cations. Also, HCs are regulated by intracellular Ca2+ concentration but in opposite direction, increasing [Ca2+]i from its resting value induces a significant opening of HCs, as measured by ATP release experiments (De

Hemichannel dysfunction in “connexinopathies”

Mutations in connexin genes have been linked to several human hereditary diseases, known as “connexinopathies” (reviewed in (Pfenniger et al., 2010)), with evidence from functional assays implicating hemichannel dysfunction in the pathogenesis of some such diseases (Table 1). Many of these mutations interfere with HC regulation by voltage and calcium.

Mutations in Cx32 and Cx47 expressed in Schwann cells and oligodendrocytes provoke disorders in peripheral and central myelin, respectively. Cx32

Concluding remarks and perspectives

There is growing evidence that the ubiquitous presence of open hemichannels in the non-junctional plasma membrane is a normal phase of the connexin life cycle. These HCs fulfill physiologically important roles and they are also activated during pathological processes. The transfer of ions and other small molecules between the cell interior and the interstitial space is dependent on the expression of solitary HCs at the cell surface, as well as their open probability, unitary conductance and

Conflict of interest statement

None of the authors have any conflict of interest.

Acknowledgments

This work was supported by grants from the Spanish Ministry of Science and Technology (SAF-2009/1164 and Consolider CSD2008-00005 to LCB) and the Community of Madrid (Neurotec-P2010/BMD-2460 to JM, LCB and DGN). J.M.G. is an investigator for FIBio-HRC supported by the Comunidad Autónoma de Madrid.

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